Abstract
Abstract 4203
Venous thrombosis (VT) is the leading cause of maternal death in the western world. Genetic causes of pregnancy related VT are insufficiently understood.
Objectives: To investigate if recently discovered associations between single nucleotide polymorphisms (SNPs) and thrombotic disease influenced the risk for pregnancy related VT. To investigate candidate genes for new associations between SNPs and pregnancy related VT.
A hospital based case control study. Cases were women with objectively verified VT during pregnancy or puerperium, controls were women giving birth without having VT. We selected 49 candidate genes involved in coagulation (35 genes), inflammation (4 genes), and hormonal metabolism (10 genes). In these genes, 463 tag-SNPs were selected from the CEU population in Hapmap and analyzed in 313 cases and 353 controls. Odds ratios for VT were calculated with the most common genotype as the reference genotype for each SNP. P-values were adjusted for multiple testing to false discovery rates.
Of the SNPs previously shown by others to be associated to thrombotic disease, rs2289252 in the FXI gene (F11), rs3917643 in the tissue factor gene (F3), rs1613662 in the glycoprotein VI gene, rs2001490 in NAT8B, rs4524 in the FV gene (F5), and rs3087505 in the prekallikrein gene were associated to pregnancy related VT. After analyzing all 463 tag-SNPs, 13 SNPs were associated to total pregnancy related VT with a false discovery rate ≤ 0.20. These SNPs belonged to F5, SELP (coding for P-selectin), F3, F8 (coding for factor VIII), and F11. When we studied antenatal and postnatal VT separately, 17 SNPs were associated with antenatal VT, while only 1 SNP was associated with postnatal VT. Thirteen SNPs in F5, SELP, or the gene for E-selectin were associated with thrombosis. After excluding carriers of factor V Leiden, 4 of these SNPs remained associated. Two SNPs in the gene for epidermal growth factor receptor (EGFR) were associated to antenatal thrombosis.
Genetic variation seems more important for antenatal than for postnatal VT. We confirmed the importance of some SNPs for the risk for pregnancy related VT, in particular rs2289252 in F11. The EGFR-gene appears to be a new genetic locus associated with pregnancy related VT.
SNPs associated with total pregnancy related VT, antenatal VT, or postnatal VT with false discovery rate ≤ 0.20.
| . | . | No (%) alleles . | . | . | |
|---|---|---|---|---|---|
| Gene . | SNP . | Controls . | Cases . | OR (CI95) . | p . |
| Total pregnancy related VT | |||||
| F5 | rs6427202 | 274 (39) | 311 (50) | 1.6 (1.3–2.0) | <0.001 |
| SELP | rs2205895 | 285 (41) | 191 (31) | 0.6 (0.5–0.8) | <0.001 |
| SELP | rs3917744 | 202 (29) | 236 (38) | 1.5 (1.2–2.0) | <0.001 |
| SELP | rs2076074 | 177 (25) | 112 (18) | 0.6 (0.5–0.8) | 0.001 |
| SELP | rs2142760 | 346 (49) | 362 (58) | 1.5 (1.2–1.8) | 0.001 |
| SELP | rs2244529 | 196 (28) | 227 (36) | 0.7 (0.5–0.9) | 0.001 |
| F5 | rs9332640 | 247 (35) | 332 (53) | 1.5 (1.2–1.8) | <0.001 |
| F11 | rs22892521–3 | 278 (39) | 281 (45) | 1.4 (1.1–1.7) | 0.003 |
| F3 | rs39176434 | 54 (8) | 23 (4) | 0.5 (0.3–0.8) | 0.002 |
| SELP | rs3917854 | 231 (33) | 160 (26) | 0.7 (0.5–0.9) | 0.003 |
| F5 | rs6427199 | 291 (41) | 201 (32) | 0.7 (0.6–0.9) | 0.002 |
| F5 | rs9332542 | 237 (34) | 163 (26) | 0.7 (0.5–0.9) | 0.002 |
| F8 | rs1472977 | 153 (22) | 98 (16) | 0.7 (0.5–0.9) | 0.003 |
| Antenatal VT | |||||
| SELP | rs2244529 | 253 (36) | 187 (60) | 0.6 (0.4–0.8) | <0.001 |
| F5 | rs6427202 | 137 (39) | 79 (1) | 1.7 (1.3–2.3) | <0.001 |
| F8 | rs1472977 | 153 (22) | 43 (14) | 0.6 (0.4–0.8) | 0.004 |
| NAT8B | rs20014902 | 240 (34) | 136 (44) | 1.5 (1.1–2.0) | 0.003 |
| SELP | rs2205895 | 285 (41) | 95 (31) | 0.6 (0.5–0.9) | 0.002 |
| SELE | rs3917410 | 77 (11) | 56 (18) | 1.8 (1.2–2.6) | 0.002 |
| SELP | rs3917744 | 202 (29) | 119 (38) | 1.6 (1.2–2.2) | 0.002 |
| F5 | rs45241 | 181 (29) | 53 (38) | 0.6 (0.4–0.8) | 0.003 |
| EGFR | rs4947491 | 252 (36) | 144 (46) | 1.5 (1.2–2.0) | 0.002 |
| SELP | rs6131 | 139 (20) | 88 (28) | 1.6 (1.2–2.1) | 0.004 |
| F5 | rs6427199 | 291 (41) | 97 (28) | 0.7 (0.5–0.9) | 0.003 |
| SELP | rs2142760 | 346 (49) | 181 (58) | 1.5 (1.1–2.0) | 0.005 |
| EGFR | rs2330951 | 170 (24) | 101 (33) | 1.5 (1.1–2.0) | 0.006 |
| NR1I2 | rs2461825 | 228 (32) | 74 (24) | 0.6 (0.5–0.9) | 0.006 |
| F3 | rs39176434 | 54 (8) | 9 (3) | 0.4 (0.2–0.7) | 0.005 |
| PROS1 | rs8178607 | 201 (29) | 64 (21) | 0.6 (0.5–0.9) | 0.007 |
| GP6 | rs16136622 | 130 (18) | 36 (12) | 0.6 (0.4–0.9) | 0.007 |
| Postnatal VT | |||||
| SELP | rs2076074 | 177 (25) | 48 (15) | 0.5 (0.4–0.7) | <0.001 |
| . | . | No (%) alleles . | . | . | |
|---|---|---|---|---|---|
| Gene . | SNP . | Controls . | Cases . | OR (CI95) . | p . |
| Total pregnancy related VT | |||||
| F5 | rs6427202 | 274 (39) | 311 (50) | 1.6 (1.3–2.0) | <0.001 |
| SELP | rs2205895 | 285 (41) | 191 (31) | 0.6 (0.5–0.8) | <0.001 |
| SELP | rs3917744 | 202 (29) | 236 (38) | 1.5 (1.2–2.0) | <0.001 |
| SELP | rs2076074 | 177 (25) | 112 (18) | 0.6 (0.5–0.8) | 0.001 |
| SELP | rs2142760 | 346 (49) | 362 (58) | 1.5 (1.2–1.8) | 0.001 |
| SELP | rs2244529 | 196 (28) | 227 (36) | 0.7 (0.5–0.9) | 0.001 |
| F5 | rs9332640 | 247 (35) | 332 (53) | 1.5 (1.2–1.8) | <0.001 |
| F11 | rs22892521–3 | 278 (39) | 281 (45) | 1.4 (1.1–1.7) | 0.003 |
| F3 | rs39176434 | 54 (8) | 23 (4) | 0.5 (0.3–0.8) | 0.002 |
| SELP | rs3917854 | 231 (33) | 160 (26) | 0.7 (0.5–0.9) | 0.003 |
| F5 | rs6427199 | 291 (41) | 201 (32) | 0.7 (0.6–0.9) | 0.002 |
| F5 | rs9332542 | 237 (34) | 163 (26) | 0.7 (0.5–0.9) | 0.002 |
| F8 | rs1472977 | 153 (22) | 98 (16) | 0.7 (0.5–0.9) | 0.003 |
| Antenatal VT | |||||
| SELP | rs2244529 | 253 (36) | 187 (60) | 0.6 (0.4–0.8) | <0.001 |
| F5 | rs6427202 | 137 (39) | 79 (1) | 1.7 (1.3–2.3) | <0.001 |
| F8 | rs1472977 | 153 (22) | 43 (14) | 0.6 (0.4–0.8) | 0.004 |
| NAT8B | rs20014902 | 240 (34) | 136 (44) | 1.5 (1.1–2.0) | 0.003 |
| SELP | rs2205895 | 285 (41) | 95 (31) | 0.6 (0.5–0.9) | 0.002 |
| SELE | rs3917410 | 77 (11) | 56 (18) | 1.8 (1.2–2.6) | 0.002 |
| SELP | rs3917744 | 202 (29) | 119 (38) | 1.6 (1.2–2.2) | 0.002 |
| F5 | rs45241 | 181 (29) | 53 (38) | 0.6 (0.4–0.8) | 0.003 |
| EGFR | rs4947491 | 252 (36) | 144 (46) | 1.5 (1.2–2.0) | 0.002 |
| SELP | rs6131 | 139 (20) | 88 (28) | 1.6 (1.2–2.1) | 0.004 |
| F5 | rs6427199 | 291 (41) | 97 (28) | 0.7 (0.5–0.9) | 0.003 |
| SELP | rs2142760 | 346 (49) | 181 (58) | 1.5 (1.1–2.0) | 0.005 |
| EGFR | rs2330951 | 170 (24) | 101 (33) | 1.5 (1.1–2.0) | 0.006 |
| NR1I2 | rs2461825 | 228 (32) | 74 (24) | 0.6 (0.5–0.9) | 0.006 |
| F3 | rs39176434 | 54 (8) | 9 (3) | 0.4 (0.2–0.7) | 0.005 |
| PROS1 | rs8178607 | 201 (29) | 64 (21) | 0.6 (0.5–0.9) | 0.007 |
| GP6 | rs16136622 | 130 (18) | 36 (12) | 0.6 (0.4–0.9) | 0.007 |
| Postnatal VT | |||||
| SELP | rs2076074 | 177 (25) | 48 (15) | 0.5 (0.4–0.7) | <0.001 |
No relevant conflicts of interest to declare.
References
Author notes
Asterisk with author names denotes non-ASH members.
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